The present invention refers to, the use of substance P antagonists particularly the invention refers to the use of NK-1 receptor antagonists for the treatment of adenocarcinomas, more particularly genito-urinary-tract neoplasms, more particularly prostatic carcinoma.
Malignant neoplasms, originating from epithelial cells are named carcinomas. A peculiar type of carcinoma, of glandular origin, is the adenocarcinomas. Since a correlation between tumors and angiogenesis has been hypothesized, a possible, effective strategy against cancer disease is a pharmacological treatment with angiogenesis inhibitors.
Angiogenesis, i.e. the formation and development of new capillary vessels, occurs in different physiologic conditions, such as embryonal development. On the other hand, intense angiogenesis occurs in several pathologic conditions, such as synovial rheumatoid hypertrophy, atherosclerosis, proliferative retinopathy and solid tumors. With reference to solid tumors, the interest in the neovascularisation has been raised from the evidence that tumors cannot growth or metastasize without new vessels and/or growth factors. Solid tumors cannot grow beyond 1-2 mm3 without neovascularation, which furnishes feeding to tumors. Therefore, experiments have been carried out in order to quantify neovascularation in order to try to evaluate the tumor growth at different stages [Tosan A., Fregene et al, Anticancer Research 13: 2377-2382 (1993); 13: Brigitte V. Offersen et al., APMIS 106: 463-469 (1998)]. Consequently, it has been hypothesized that tumor growth could be prevented by neovascularization blockage.
Experimental evidences have recently outlined that substance P (SP) plays a role in angiogenesis stimulation:
Daily administration of substance P causes intense neovascularization in a rat sponge model of angiogenesis [T.-P. D. Fan et al, Br. J. Pharmacol. 110: 43-49 (1993)];
The angiogenic response towards SP can be blocked by using selective antagonists for NK-1 receptors for tachykinines [T.-P. D. Fan et al, Br. J. Pharmacol. 110: 43-49 (1993)];
The angiogenic activity of SP can be counteracted by administration of either peptide or non peptide antagonists [D. Regoli et al., Pharmacol. Rev., Vol. 64, No. 4 551-559 (1994)].
EP 0835662 describes peptide antagonists of substance P which are characterized by negative side effects. Henning Ivo M. et al., Int. J. Cancer. 61, 786-792 (1995) describes binding experiments for substance P receptors and hypothesizes that the progression of tumor is mediated via angiogenetic mechanisms.
Such experimental results have not yet led to identify any drug which could be successfully employed in the treatment of the adenocarcinomas, particularly the prostatic carcinoma. As a matter of fact, Fan et al. states about future therapeutic applications in the above mentioned mechanism.
Moreover, NK-1 antagonists show a great variability in their molecular structure (Regoli et al, 1994), therefore being very difficult to predict potential activity based upon their structure-activity relationship. Also, insofar, no data have currently shown that the antagonistic activity and selectivity towards the human subtype NK-1 receptor could be of interest in the therapy of adenocarcinoma, particularly of the prostatic adenocarcinoma. In relation to the current state of the art regarding cancer therapy, none of the tested substances seems to be effective in cancer therapy. Therefore for the substances mentioned in Regoli it cannot be inferred any specific activity against cancer.
With the present invention, we aim at inhibiting, via administration of inhibitors of angiogenesis and particularly by using of antagonists of NK-1 tachykinergic receptor, solid tumor growth specifically localized to the genito-urinary tract. This innovative methodology either substitutes or integrates current therapies against cancer, such as surgery, chemiotherapy and radiotherapy.
It is an object of the present invention the use of NK-1 receptor antagonists in the treatment of the adenocarcinomas, particularly in the treatment of the carcinomas of the genito-urinary tract and more particularly in the treatment of the prostatic adenocarcinoma.
Another object of the invention is the use of substance P antagonists in the treatment of the adenocarcinomas, particularly in the treatment of the carcinomas of the genito-urinary tract and more particularly in the treatment of the prostatic adenocarcinoma.